The sensory nervous system innervates mucosal tissues that are highly exposed to pathogenic organisms. Pain is a major symptom of patients suffering from infectious diseases. During tissue inflammation, nociceptors, the neurons which react to intense/damaging stimuli, are excited, leading to a state of hyper-algesia. The role of pain-sensing fibers in host-pathogen defense has not been elucidated. In this study, we propose that the nervous system plays an active role in the detection and defense against bacterial infection. We find that nociceptor neurons can directly recognize and respond to two major bacterial ligands, N-formyl-Met-Leu-Phe (fMLF) and Lipopolysaccharide (LPS). Nociceptor neurons express the co-receptors for LPS, CD14 and Toll-like Receptor 4 (TLR4). Therefore, sensory neurons may share similar pathogen recognition pathways as the innate immune system. In Specific Aim 1 and Aim 2, I will investigate the receptor signaling pathways that mediate the recognition of fMLF and LPS by pain-sensing neurons. Upon stimulation, peripheral nociceptor fibers release neuro-peptides including CGRP and substance P, which act on endothelial and smooth muscle cells to induce vaso-dilation. This leads to the influx of inflammatory mediators and recruitment of innate immune cells. The role of this neurogenic inflammation has not ben analyzed in the context of infection. We propose that pain mediated inflammation plays an important role in limiting the invasion and spread of pathogens. In Specific Aim 3, I will investigate the relevance of neurogenic inflammation in the defense against bacterial infection. We will generate C- fiber nociceptor neuron deficient mice, which lack the ability to produce neuropeptides, and neuronal conditional knockout mice for MyD88, the downstream signaling adaptor for all Toll-like Receptors. These mice will be tested in two clinically relevant models of LPS induced endotoxemia and Streptococcus Pneumoniae bacterial infection. A direct pathogen detection mechanism by sensory neurons indicates remarkable similarities between innate immunity and nociception. Activation of pain neurons may directly efectuate the host inflammatory response to pathogens. Elucidating the molecular pathways that mediate this process will benefit the future treatment of pain and infectious disease.